Effects of laterally wedged insoles on symptoms and disease progression in medial knee osteoarthritis: a protocol for a randomised, double-blind, placebo controlled trial

Background: Whilst laterally wedged insoles, worn inside the shoes, are advocated as a simple, inexpensive, non-toxic self-administered intervention for knee osteoarthritis (OA), there is currently limited evidence to support their use. The aim of this randomised, double-blind controlled trial is to determine whether laterally wedges insoles lead to greater improvements in knee pain, physical function and health-related quality of life, and slower structural disease progression as well as being more cost-effective, than control flat insoles in people with medial knee OA.

Methods/Design: Two hundred participants with painful radiographic medial knee OA and varus malalignment will be recruited from the community and randomly allocated to lateral wedge or control insole groups using concealed allocation. Participants will be blinded as to which insole is considered therapeutic. Blinded follow up assessment will be conducted at 12 months after randomisation. The outcome measures are valid and reliable measures recommended for OA clinical trials. Questionnaires will assess changes in pain, physical function and health-related quality-of-life. Magnetic resonance imaging will measure changes in tibial cartilage volume. To evaluate cost-effectiveness, participants will record the use of all health-related treatments in a log-book returned to the assessor on a monthly basis. To test the effect of the intervention using an intention-to-treat analysis, linear regression modelling will be applied adjusting for baseline outcome values and other demographic characteristics.

Discussion: Results from this trial will contribute to the evidence regarding the effectiveness of laterally wedged insoles for the management of medial knee OA.

Trial registration: ACTR12605000503628; NCT00415259.

Age does not influence the bone response to treadmill exercise in female rats

Purpose: Because it is believed that bone may respond to exercise differently at different ages, we compared bone responses in immature and mature rats after 12 wk of treadmill running.

Methods: Twenty-two immature (5-wk-old) and 21 mature (17-wk-old) female Sprague Dawley rats were randomized into a running (trained, N = 10 immature, 9 mature) or a control group (controls, N = 12 immature, 12 mature) before sacrifice 12 wk later. Rats ran on a treadmill five times per week for 60-70 min at speeds up to 26 m[middle dot]min-1. Both at baseline and after intervention, we measured total body, lumbar spine, and proximal femoral bone mineral, as well as total body soft tissue composition using dual-energy x-ray absorptiometry (DXA) in vivo. After sacrificing the animals, we measured dynamic and static histomorphometry and three-point bending strength of the tibia.

Results: Running training was associated with greater differences in tibial subperiosteal area, cortical cross-sectional area, peak load, stiffness, and moment of inertia in immature and mature rats (P < 0.05). The trained rats had greater periosteal bone formation rates (P < 0.01) than controls, but there was no difference in tibial trabecular bone histomorphometry. Similar running-related gains were seen in DXA lumbar spine area (P = 0.04) and bone mineral content (BMC;P = 0.03) at both ages. For total body bone area and BMC, the immature trained group increased significantly compared with controls (P < 0.05), whereas the mature trained group gained less than did controls (P < 0.01).

Conclusion: In this in vivo model, where a similar physical training program was performed by immature and mature female rats, we demonstrated that both age groups were sensitive to loading and that bone strength gains appeared to result more from changes in bone geometry than from improved material properties.

Relationship of nutritional and metabolic factors to non-invasive indices of macrovascular disease in diabetes

Factors which may account for the high frequency of macrovascular disease in diabetics are age, sex, cigarette smoking, hypertension, obesity, lack of exercise, diet, hyperglycaemia, hyperinsulinaeroia, hypercholesterolaemia, hypertriglyceridaemia, low HDL-cholesterol concentration, elevated free fatty acid concentration and enhanced platelet aggregation. Twenty seven (13 men and 14 women) non-insulin-dependent diabetics and thirty eight age, height and weight matched healthy subjects (10 men and 28 women) were studied. None of the subjects were smokers, or hypertensive. No subject had any clinical evidence of peripheral arterial disease, coronary heart disease or cerebrovascular disease. All had apparently normal peripheral pulses and normal ankle/arm blood pressure indices. Methods for determining arterial compliance in the segment between the left subclavian artery and each common femoral artery, and proximal resistance at the common femoral artery and posterior tibial artery, have been reviewed and developed. An appropriate food intake methodology for deriving food indices from food records was developed. Biochemical determinants have been made of glucose tolerance, glycosylated haemoglobin, serum total cholesterol, HDL-cholesterol, LDL-cholesterol, triglyceride, plasma free fatty acid and insulin. A significant decrease in the arterial compliance, and a significant increase in the arterial proximal resistance at the common femoral artery and posterior tibial artery in non-insulin-dependent diabetics, compared with their healthy controls, have been found. Significant negative correlation between arterial compliance and proximal resistance and, a significant positive correlation between the arterial proximal resistance of common femoral artery and posterior tibial artery were found. Differences between control (healthy subjects) and non-insulin-dependent diabetic groups indicate that preclinical peripheral arterial disease can be recognised even in mild diabetics by non-invasive measurement of arterial compliance or proximal resistance. There were significant and negative correlations between arterial compliance and each of blood glucose, blood glycosylated haemoglobin (HbAlC), plasma free fatty acid and plasma insulin concentration. There were significant and positive correlations between arterial proximal resistance of common femoral artery and posterior tibial artery and each of blood glucose, glycosylated haemoglobin and plasma free fatty acid concentration. Multivariate analysis to examine each of the biochemical factors Including blood glucose, blood glycosylated haemoglobin (HbAlC), plasma free fatty acid, plasma Insulin and lipids, showed that the factor which most influenced the arterial compliance and the proximal resistance of posterior tibial artery was the glucose level in the fasting state or the glucose response after a glucose load. In addition, the factors which most influenced proximal resistance of the common femoral artery were free fatty acid -level in the fasting state or glucose response after a glucose load. The factors which most influenced arterial compliance were glucose level in men, and the insulin level in the fasting state or the plasma free fatty acid response after a glucose load in women. These findings indicate that blood glucose, plasma free fatty acid and plasma insulin are risk factors for changes in arterial wall characteristic at a stage when no clinical evidence of macrovascular disease is apparent. Arterial compliance was decreased and the proximal resistance of posterior tibial artery was increased in those with a low intake of protective foods compared with those with a high intake whether healthy subjects or non-insulin-dependent diabetics. Arterial compliance was decreased in non-fish eaters compared with the fish eaters whether healthy subjects or non-insulin-dependent diabetics. Proximal resistance of the posterior tibia! artery in non-fish eaters was increased compared with fish eaters in healthy subjects. Overall, food variety, a protective food score consumption and fish consumption emerge as importance determinants of arterial wall characteristics at a stage when no clinical evidence of macrovascular disease is apparent.

A full body musculoskeletal model based on flexible multibody simulation approach utilised in bone strain analysis during human locomotion

Load-induced strains applied to bone can stimulate its development and adaptation. In order to quantify the incident strains within the skeleton, in vivo implementation of strain gauges on the surfaces of bone is typically used. However, in vivo strain measurements require invasive methodology that is challenging and limited to certain regions of superficial bones only such as the anterior surface of the tibia. Based on our previous study [Al Nazer et al. (2008) J Biomech. 41:1036–1043], an alternative numerical approach to analyse in vivo strains based on the flexible multibody simulation approach was proposed. The purpose of this study was to extend the idea of using the flexible multibody approach in the analysis of bone strains during physical activity through integrating the magnetic resonance imaging (MRI) technique within the framework. In order to investigate the reliability and validity of the proposed approach, a three-dimensional full body musculoskeletal model with a flexible tibia was used as a demonstration example. The model was used in a forward dynamics simulation in order to predict the tibial strains during walking on a level exercise. The flexible tibial model was developed using the actual geometry of human tibia, which was obtained from three-dimensional reconstruction of MRI. Motion capture data obtained from walking at constant velocity were used to drive the model during the inverse dynamics simulation in order to teach the muscles to reproduce the motion in the forward dynamics simulation. Based on the agreement between the literature-based in vivo strain measurements and the simulated strain results, it can be concluded that the flexible multibody approach enables reasonable predictions of bone strain in response to dynamic loading. The information obtained from the present approach can be useful in clinical applications including devising exercises to prevent bone fragility or to accelerate fracture healing.

Cross-sectional geometry of weight-bearing tibia in female athletes subjected to different exercise loadings

Summary The association of long-termsport-specific exercise loading with cross-sectional geometry of the weight-bearing tibia was evaluated among 204 female athletes representing five different exercise loadings and 50 referents. All exercises involving ground impacts (e.g., endurance running, ball games, jumping) were associated with thicker cortex at the distal and diaphyseal sites of the tibia and also with large diaphyseal cross-section, whereas the high-magnitude (powerlifting) and non-impact (swimming) exercises were not. Introduction Bones adapt to the specific loading to which they are habitually subjected. In this cross-sectional study, the association of long-term sport-specific exercise loading with the geometry of the weight-bearing tibia was evaluated among premenopausal female athletes representing 11 different sports.

Methods A total of 204 athletes were divided into five exercise loading groups, and the respective peripheral quantitative computed tomographic data were compared to data obtained from 50 physically active, non-athletic referents. Analysis of covariance was used to estimate the between-group differences.

Results At the distal tibia, the high-impact, odd-impact, and repetitive low-impact exercise loading groups had ~30% to 50% (p<0.05) greater cortical area (CoA) than the referents. At the tibial shaft, these three impact groups had ~15% to 20% (p<0.05) greater total area (ToA) and ~15% to 30% (p<0.05) greater CoA. By contrast, both the high-magnitude and repetitive non-impact groups had similar ToA and CoA values to the reference group at both tibial sites.

Conclusions High-impact, odd-impact, and repetitive lowimpact exercise loadings were associated with thicker cortex at the distal tibia. At the tibial shaft, impact loading was not only associated with thicker cortex, but also a larger cross-sectional area. High-magnitude exercise loading did not show such associations at either site but was comparable to repetitive non-impact loading and reference data. Collectively, the relevance of high strain rate together with moderate-to-high strain magnitude as major determinants of osteogenic loading of the weight-bearing tibia is implicated.

Neuromuscular performance and bone structural characteristics in young healthy men and women

Muscle mass and strength have been shown to be important factors in bone strength. Low muscular force predisposes to falling especially among elderly. Regular exercise helps to prevent falls and resulting bone fractures. Better understanding of muscle function and its importance on bone properties may thus add information to fracture prevention. Therefore the purpose of this study was to examine the relationship between bone strength and muscular force production. Twenty-young men [24 (2) years] and 20 [24 (3) years] women served as subjects. Bone compressive (BSId) and bending strength indices (50 Imax) were measured with peripheral quantitative computed tomography (pQCT) at tibial mid-shaft and at distal tibia. Ankle plantarflexor muscle volume (MV) was estimated from muscle thickness measured with ultrasonography. Neuromuscular performance was evaluated from the measurements of maximal ground reaction force (GRF) in bilateral jumping and of eccentric maximal voluntary ankle plantarflexor torque (MVC). Specific tension (ST) of the plantarflexors was calculated by dividing the MVC with the muscle volume. Activation level (AL) was measured with superimposed twitch method. Distal tibia BSId and tibial mid-shaft 50 Imax correlated positively with GRF, MVC and MV in men (r = 0.45–0.67, P\0.05). Tibial mid-shaft 50 Imax and neuromuscular performance variables were correlated in women (r = 0.46–0.59, P\0.05), whereas no correlation was seen in distal tibia. In the regression analysis, MV and ST could explain 64% of the variance in tibial mid-shaft bone strength and 41% of the variation in distal tibia bone strength. The study emphasizes that tibial strength is related to maximal neuromuscular performance. In addition, tibial mid-shaft seems to be more dependent on the neuromuscular performance, than distal tibia. In young adults, the association between bone adaptation and neuromuscular performance seems to be moderate and also site and loading specific.

Direction-specific diaphyseal geometry and mineral mass distribution of tibia and fibula: A pQCT study of female athletes representing different exercise loading types

Bones adapt to prevalent loading, which comprises mainly forces caused by muscle contractions. Therefore, we hypothesized that similar associations would be observed between neuromuscular performance and rigidity of bones located in the same body segment. These associations were assessed among 221 premenopausal women representing athletes in high-impact, odd-impact, highmagnitude, repetitive low-impact, and repetitive nonimpact sports and physically active referents aged 17–40 years. The whole group mean age and body mass were 23 (5) and 63 (9) kg, respectively. Bone cross sections at the tibial and fibular mid-diaphysis were assessed with peripheral quantitative computed tomography (pQCT). Density-weighted polar section modulus (SSI) and minimal and maximal crosssectional moments of inertia (Imin, Imax) were analyzed. Bone morphology was described as the Imax/Imin ratio. Neuromuscular performance was assessed by maximal power during countermovement jump (CMJ). Tibial SSI was 31% higher in the high-impact, 19% in the odd-impact, and 30% in the repetitive low-impact groups compared with the reference group (P\0.005). Only the high-impact group differed from the referents in fibular SSI (17%, P\0.005). Tibial morphology differed between groups (P = 0.001), but fibular morphology did not (P = 0.247). The bone-bygroup interaction was highly significant (P\0.001). After controlling for height, weight, and age, the CMJ peak power correlated moderately with tibial SSI (r = 0.31, P\0.001) but not with fibular SSI (r = 0.069, P = 0.313). In conclusion, observed differences in the association between neuromuscular performance and tibial and fibular traits suggest
that the tibia and fibula experience different loading

An open source approach for regional cortical bone mineral density analysis

Objective: Cortical porosity, particularly at the endocortical region, is recognised to play a central role in the pathogenesis of bone fragility. Therefore, the purpose of this study was to: 1) demonstrate how cortical volumetric BMD (vBMD) distribution can be analysed from (p)QCT images and 2) highlight the clinical significance of assessing regional density distribution of cortical bone. 

Methods: We used pQCT to compare mid-tibial cortical volumetric BMD distribution of 20 young (age 24(SD2) years, mass 77(11) kg, height 178(6) cm) and 25 elderly (72(4) years, 75(9) kg, 172(5) cm) men. Radial and polar cortical vBMD distributions were analysed using a custom built open source analysis tool which allowed the cortex to be divided into three concentric cortical divisions and in 36 cortical sectors originating from the centroid of the bone.

Results: Mean vBMD did not differ between the groups (1135(16) vs. 1130(28) mg/cm, P=0.696). In contrast, there was a significant age-group by radial division interaction for radial cortical vBMD (P<0.001).

Conclusions: The proposed analysis method for analysing cortical bone density distribution of pQCT images was effective for detecting regional differences in cortical density between young and elderly men, which would have been missed by just looking at mean vBMD values.

Does an increase in body mass index over 10 years affect knee structure in a population-based cohort study of adult women?

Introduction : Although obesity is a modifiable risk factor for knee osteoarthritis (OA), the effect of weight gain on knee structure in young and healthy adults has not been examined. The aim of this study was to examine the relationship between body mass index (BMI), and change in BMI over the preceding 10-year period, and knee structure (cartilage defects, cartilage volume and bone marrow lesions (BMLs)) in a population-based sample of young to middle-aged females.

Methods : One hundred and forty-two healthy, asymptomatic females (range 30 to 49 years) in the Barwon region of Australia, underwent magnetic resonance imaging (MRI) during 2006 to 2008. BMI measured 10 years prior (1994 to 1997), current BMI and change in BMI (accounting for baseline BMI) over this period, was assessed for an association with cartilage defects and volume, and BMLs.

Results : After adjusting for age and tibial plateau area, the risk of BMLs was associated with every increase in one-unit of baseline BMI (OR 1.14 (95% CI 1.03 to 1.26) P = 0.009), current BMI (OR 1.13 (95% CI 1.04 to 1.23) P = 0.005), and per one unit increase in BMI (OR 1.14 (95% CI 1.03 to 1.26) P = 0.01). There was a trend for a one-unit increase in current BMI to be associated with increased risk of cartilage defects (OR 1.06 (95% CI 1.00 to 1.13) P = 0.05), and a suggestion that a one-unit increase in BMI over 10 years may be associated with reduced cartilage volume (-17.8 ml (95% CI -39.4 to 3.9] P = 0.10). Results remained similar after excluding those with osteophytes.

Conclusions : This study provides longitudinal evidence for the importance of avoiding weight gain in women during early to middle adulthood as this is associated with increased risk of BMLs, and trend toward increased tibiofemoral cartilage defects. These changes have been shown to precede increased cartilage loss. Longitudinal studies will show whether avoiding weight gain in early adulthood may play an important role in diminishing the risk of knee OA.

An application of the flexible multibody approach used to estimate human skeleton loading

Skeletal loading can be estimated using several approaches. The most common approach is based on utilizing mechanical principles and ground reaction forces as predictors for skeletal loading. This method can be considered as a relatively simple approach since it cannot account for muscle forces. Flexible multibody approach allows for estimating skeletal loading and strains within the bones; once bone flexibility, muscle forces, ground reaction forces and the natural motion of a subject have been accounted for. This paper presents a summary that describes how deformable bodies can be introduced to the standard multibody formulation and explains the benefits and drawbacks. As an example of application, models used to assess tibial strains among two subjects are presented. The results of the multibody simulations are compared to in vivo studies, showing acceptable correlation and method performance.

Transfection of MDA-MB-231 human breast carcinoma cells with bone sialoprotein (BSP) stimulates migration and invasion in vitro and growth of primary and secondary tumors in nude mice

We have investigated the role of bone sialoprotein (BSP), a secreted glycoprotein normally found in bone, in breast cancer progression. To explore functions for BSP in human breast cancer invasion and metastasis, the full-length BSP cDNA was transfected into the MDA-MB-231-BAG human breast cancer cell line under the control of the CMV promoter. Clones expressing BSP and vector control clones were isolated. BSP producing clones showed increased monolayer wound healing, a faster rate of stellate outgrowth in Matrigel and increased rate of invasion into a collagen matrix when compared to control clones. Clones were also examined in models of breast cancer growth and metastasis in vivo. BSP transfected clones showed an increased rate of primary tumor growth following mammary fat pad injection of nude mice. BSP transfected clones and vector control clones metastasized to soft organs and bone at a similar rate after intra-cardiac injection as determined by real-time PCR and X-ray analysis. Although these organs were targets for both BSP transfected and non-transfected cells, the size of the metastatic lesion was shown to be significantly larger for BSP expressing clones. This was determined by real-time PCR analysis for soft organs and by X-ray analysis of bone lesions. For bone this was confirmed by intra-tibial injections of cells in nude mice. We conclude that BSP acts to drive primary and secondary tumor growth of breast cancers in vivo.

Relationship between lower limb neuromuscular performanceand bone strength in postmenopausal women with mild knee osteoarthritis

Objectives: To investigate whether neuromuscular performance predicts lower limb bone strength in different lower limb sites in postmenopausal women with mild knee osteoarthritis (OA). Methods: Neuromuscular performance of 139 volunteer women aged 50-68 with mild knee OA was measured using maximal counter movement jump test, isometric knee flexion and extension force and figure-of-eight-running test. Femoral neck section modulus (Z, mm3) was determined by data obtained from dualenergy X-ray absorptiometry. Data obtained using peripheral quantitative computed tomography was used to asses distal tibia compressive (BSId, g2/cm4) and tibial mid-shaft bending (SSImaxmid, mm3) strength indices. Results: After adjustment for height, weight and age, counter movement jump peak power production was the strongest independent predictor for Z (β=0.44; p<0.001) and for BSId (β=0.32; p=0.003). This was also true in concentric net impulse for Z (β=0.37; p=0.001) and for BSId (β=0.40; p<0.001). Additionally, knee extension force (β=0.30; p<0.001) and figure-of-eight-running test (β= -0.32; p<0.001) were among strongest independent predictors for BSId after adjustments. For SSImaxmid, concentric net impulse (β=0.33; p=0.002) remained as the strongest independent predictor after adjustments. Conclusions: Neuromuscular performance in postmenopausal women with mild knee OA predicted lower limb bone strength in every measured skeletal site.

Persisting side-to-side differences in bone mineral content, but not in muscle strength and tendon stiffness after anterior cruciate ligament reconstruction

Tendon stiffness may be involved in limiting peak musculoskeletal forces and thus may constitute an upper limit for bone strength. The patellar tendon bone (PTB) graft, which is harvested from the patellar tendon during surgical reconstruction of the anterior cruciate ligament (ACL), is an ideal scenario to test this hypothesis. Eleven participants were recruited who had undergone surgical reconstruction of the ACL with a PTB graft 1-10 years prior to study inclusion. As previously reported, there was no side-to-side difference in thigh muscle cross-sectional area, in maximum voluntary knee extension torque, or in patellar tendon stiffness, suggesting full recovery of musculature and tendon. However, in the present study bone mineral content (BMC), assessed by peripheral quantitative computed tomography, was lower on the operated side than on the control side in four regions studied (P = 0·0019). Differences were less pronounced in the two sites directly affected by the operation (patella and tibia epiphysis) when compared to the more remote sites. Moreover, significant side-to-side differences were found in BMC in the trabecular compartment in the femoral and tibial epiphysis (P = 0·004 and P = 0·047, respectively) with reductions on the operated side, but increased in the patella (P = 0·00016). Cortical BMC, by contrast, was lower on the operated side at all sites except the tibia epiphysis (P = 0·09). These findings suggest that impaired recovery of BMC following ACL reconstruction is not because of lack of recovery of knee extensor strength or patellar tendon stiffness. The responsible mechanisms still remain to be determined.

Evidence for an additional effect of whole-body vibration above resistive exercise alone in preventing bone loss during prolonged bed rest

SUMMARY: The addition of whole-body vibration to high-load resistive exercise may provide a better stimulus for the reduction of bone loss during prolonged bed rest (spaceflight simulation) than high-load resistive exercise alone. INTRODUCTION: Prior work suggests that the addition of whole-body vibration to high-load resistive exercise (RVE) may be more effective in preventing bone loss in spaceflight and its simulation (bed rest) than resistive exercise alone (RE), though this hypothesis has not been tested in humans. METHODS: Twenty-four male subjects as part of the 2nd Berlin Bed Rest Study performed RVE (n = 7), RE (n = 8) or no exercise (control, n = 9) during 60-day head-down tilt bed rest. Whole-body, spine and total hip dual X-ray absorptiometry (DXA) measurements as well as peripheral quantitative computed tomography measurements of the tibia were conducted during bed rest and up to 90 days afterwards. RESULTS: A better retention of bone mass in RVE than RE was seen at the tibial diaphysis and proximal femur (p ≤ 0.024). Compared to control, RVE retained bone mass at the distal tibia and DXA leg sub-region (p ≤ 0.020), but with no significant difference to RE (p ≥ 0.10). RE impacted significantly (p = 0.038) on DXA leg sub-region bone mass only. Calf muscle size was impacted similarly by both RVE and RE. On lumbar spine DXA, whole-body DXA and calcium excretion measures, few differences between the groups were observed. CONCLUSIONS: Whilst further countermeasure optimisation is required, the results provide evidence that (1) combining whole-body vibration and high-load resistance exercise may be more efficient than high-load resistive exercise alone in preventing bone loss at some skeletal sites during and after prolonged bed rest and (2) the effects of exercise during bed rest impact upon bone recovery up to 3 months afterwards.

Estimation of changes in volume of individual lower-limb muscles using magnetic resonance imaging (during bed-rest)

Muscle size in the lower limb is commonly assessed in neuromuscular research as it correlates with muscle function and some approaches have been assessed for their ability to provide valid estimates of muscle volume. Work to date has not examined the ability of different measurement approaches (such as cross-sectional area (CSA) measures on magnetic resonance (MR) imaging) to accurately track changes in muscle volume as a result of an intervention, such as exercise, injury or disuse. Here we assess whether (a) the percentage change in muscle CSA in 17 lower-limb muscles during 56 days bed-rest, as assessed by five different algorithms, lies within 0.5% of the muscle volume change and (b) the variability of the outcome measure is comparable to that of muscle volume. We find that an approach selecting the MR image with the highest muscle CSA and then a series of CSA measures, the number of which depended upon the muscle considered, immediately distal and proximal, provided an acceptable estimate of the muscle volume change. In the vastii, peroneal, sartorius and anterior tibial muscle groups, accurate results can be attained by increasing the spacing between CSA measures, thus reducing the total number of MR images and hence the measurement time. In the two heads of biceps femoris, semimembranosus and gracilis, it is not possible to reduce the number of CSA measures and the entire muscle volume must be evaluated. Using these approaches one can reduce the number of CSA measures required to estimate changes in muscle volume by ~60%. These findings help to attain more efficient means to track muscle volume changes in interventional studies.